The goal of the UCLA-CGEP is to investigate the hypothesis that the cellular mechanisms of action identified for Putative Environmental Toxicants (PETs) contribute to a significant increase in PD risk; this project will focus on investigations in humans. Our group identified specific cellular mechanisms that are affected by PETs: the proteasome, microtubule integrity, and aldehyde dehydrogenase detoxification. In conjunction with altered VMAT function/expression that influences dopamine balance, these pathways may affect the vulnerability of DA neurons to neurodegeneration. We propose to use our existing data from the Parkinson Environment Gene (PEG) study to test biological candidate genes and PETs for association with PD. We have enrolled nearly 400 PD patients and 400 population controls from California's Central Valley. Each individual has been assessed for pesticide exposure based on records mandated by state law, and patients have been examined by a UCLA Movement Disorder neurologist, thus, we have a unique resource of well characterized PD subjects and controls with exceptional data for exposure to specific agricultural pesticides. To detect associations for rarer pesticides and genetic variants acting in the hypothesized biological pathways and to investigate gene-gene (GxG) and gene-environment (GxE) interactions with sufficient power, we propose to recruit and collect biological (DMA) samples from 400 additional population controls as a quick and cost-effective way to increase sample size and power. Our specific aims are to test the hypotheses that 1) environmental pesticides targeting the same cellular systems as the previously identified PETs also increase PD risk; 2) variants of genes (assessed via putative functional and haplotype tagging SNPs) in cellular pathways affected by PETs increase PD risk. Secondarily, we will a) test GxE and GxG interactions (including VMAT) to determine whether variants of the candidate genes selected interact with PETs and/or other genes to modulate PD risk in humans; b) retest genetic and GxG interaction associations in a replication cohort. Genes selected for initial investigation in this project have been determined by data~ on pathways and genes from our basic science projects (projects 1-3). Genetic investigations in later years of this project will be driven by the initial results of projects 1-3 in this center. In turn, the findings from gene and PET investigations in this human study will feedback and help develop hypotheses to be tested in the other projects.